Hydrogel-Based Glucose Sensors: Effects of Phenylboronic Acid Chemical Structure on Response

Abstract

Phenylboronic acids (PBAs) are being considered for glucose sensing and controlled insulin release, because of their affinity for diol-containing molecules. The interaction of immobilized PBAs in a hydrogel matrix with glucose can lead to volumetric changes that have been used to monitor glucose concentration and release insulin. Although the interaction of PBAs with diol-containing molecules has been intensively studied, the response of PBA-modified hydrogels as a function of the specific PBA chemistry is not well understood. To understand the interaction of immobilized PBAs with glucose in hydrogel systems under physiological conditions, the glucose-dependent volumetric changes of a series of hydrogel sensors functionalized with different classes of PBAs were investigated. The volume change induced by PBA-glucose interactions is converted to the diffracted wavelength shift by a crystalline colloidal array embedded in the hydrogel matrix. The PBAs studied contain varying structural parameters such as the position of the boronic acid on the phenyl ring, different substituents on PBAs and different linkers to the hydrogel backbone. The volumetric change of the PBA modified hydrogels is found to be highly dependent on the chemical structure of the immobilized PBAs. The PBAs that appear to provide linear volumetric responses to glucose are found to also have slow response kinetics and significant hysteresis, while PBAs that show nonlinear responses have fast response kinetics and small hysteresis. Electron-withdrawing substituents, which reduce the pK a of PBAs, either increase or decrease the magnitude of response, depending on the exact chemical structure. The response rate is increased by PBAs with electronwithdrawing substituents. Addition of a methylene bridge between the PBA and hydrogel backbone leads to a significant decrease in the response magnitude. PBAs with specific desirable features can be selected from the pool of available PBAs and other PBA derivatives with desired properties can be designed according to the findings reported here.

Glucose‐Sensitive Hydrogel Optical Fibers Functionalized with Phenylboronic Acid

“…[25] The formation of boronate anions upon glucose-3-APBA complexation increases the Donnan osmotic pressure of the hydrogel fiber. [26] …”

“…[13c] In contrast to the photonic crystal sensors that only expand in z-direction, hydrogel optical fibers expand isotropically. [26] Unlike enzymatic reactions involving glucose oxidase or hexokinase-glucose-6-phosphate dehydrogenase, [34] 3-APBA competitively bind cis diols of carbohydrates ( e.g. , fructose) as well as lactate through its α-hydroxy acids.…”

“…Electron-withdrawing substituents may increase the sensor response by decreasing the p K a of PBA. [26] One of the factors that affected the sensing time was the diffusion rate of the glucose molecules into the optical hydrogel fibers. Other phenylboronic acid functionalized high-surface area copolymer geometries such as microgel particles [11, 39] and porous thin films [40] can be utilized to improve the responsivity to glucose within the hydrogel optical fiber platform for achieving faster equilibrium.…”

Impedance spectroscopy for monosaccharides detection using responsive hydrogel modified paper-based electrodes

“…Introduction of a crystalline colloidal array embedded in a similar PBA hydrogel matrix allows for volume changes induced by PBA--glucose interactions to be converted in a wavelength shift of the Bragg diffracted light. 29 Just recently, a PBA hydrogel was used in a MEMS capacitive transducer, in order to measure the changes in the dielectric properties of the hydrogel upon sugar binding 30. In this case, the PBA hydrogel was sandwiched between two parallel thin--film micro--electrodes fabricated by photo--lithography.…”

Toward biomaterial-based implantable photonic devices

“…The change in the reflection can be measured through the skin or by an optical fiber with reflection spectrometer and correlated with the concentration [95]. Photonic crystals can be functionalized to become sensitive to a wide range of physiologically relevant analytes such as Pb 2+ ions [96,97], urea [98], glucose [99], creatinine [100], and ammonia [101] and pH in the physiological range (4.5-9.0) [102,103]. Glucose sensing with photonic crystals has been demonstrated with a detection limit of~100 µM in the solution [104] and tear fluid [105].…”